chr16-31109395-G-A

Variant names:

• chr16-31109395-G-A
• rs2057390809
• NM_005881.4:c.172G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005881.4(BCKDK):​c.172G>A​(p.Ala58Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BCKDK NM_005881.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

Genes affected

BCKDK (HGNC:16902): (branched chain keto acid dehydrogenase kinase) The branched-chain alpha-ketoacid dehydrogenase complex (BCKD) is an important regulator of the valine, leucine, and isoleucine catabolic pathways. The protein encoded by this gene is found in the mitochondrion, where it phosphorylates and inactivates BCKD. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22354054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDK	NM_005881.4	c.172G>A	p.Ala58Thr	missense_variant	Exon 2 of 12	ENST00000219794.11	NP_005872.2
BCKDK	NM_001122957.4	c.172G>A	p.Ala58Thr	missense_variant	Exon 2 of 11		NP_001116429.1
BCKDK	NM_001271926.3	c.172G>A	p.Ala58Thr	missense_variant	Exon 2 of 10		NP_001258855.1
BCKDK	XM_017022859.2	c.172G>A	p.Ala58Thr	missense_variant	Exon 2 of 12		XP_016878348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDK	ENST00000219794.11	c.172G>A	p.Ala58Thr	missense_variant	Exon 2 of 12	1	NM_005881.4	ENSP00000219794.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455604 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 723184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172G>A (p.A58T) alteration is located in exon 2 (coding exon 1) of the BCKDK gene. This alteration results from a G to A substitution at nucleotide position 172, causing the alanine (A) at amino acid position 58 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;T;.;T;.
Eigen	Benign	-0.092
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	.;D;D;D;T;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;L;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.99	N;N;N;N;D;D;N
REVEL	Benign	0.075
Sift	Benign	0.32	T;T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T;T
Polyphen		0.0030	B;.;.;B;.;.;.
Vest4		0.27
MutPred		0.25		Gain of phosphorylation at A58 (P = 0.0519);Gain of phosphorylation at A58 (P = 0.0519);Gain of phosphorylation at A58 (P = 0.0519);Gain of phosphorylation at A58 (P = 0.0519);Gain of phosphorylation at A58 (P = 0.0519);Gain of phosphorylation at A58 (P = 0.0519);Gain of phosphorylation at A58 (P = 0.0519);
MVP		0.54
MPC		0.55
ClinPred		0.78	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2057390809; hg19: chr16-31120716;